CN106361793A - 一种提高复方茵陈注射液安全性药物组合物的制备方法 - Google Patents
一种提高复方茵陈注射液安全性药物组合物的制备方法 Download PDFInfo
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Abstract
本发明公布了一种提高复方茵陈注射液安全性药物组合物的制备方法,该药物组合物主要由茵陈提取物、春柴胡提取物、三七提取物和聚乙二醇十五羟基硬脂酸酯制成的供注射用药物组合物。本发明采用安全性更好、助溶效果更明显的助溶剂替换复方茵陈注射液中存在安全隐患和影响产品质量的助溶剂聚山梨酯80,聚乙二醇十五羟基硬脂酸酯的安全性比聚山梨酯80高而且用量更低,减少药物发生不良反应的几率和风险,提高临床用药的安全性。
Description
技术领域
本发明属于医药技术领域,具体地,涉及一种提高复方茵陈注射液安全性药物组合物的制备方法。
背景技术
复方茵陈注射液标准收载于卫生部颁药品标准(中药成方制剂),原料药为茵陈、春柴胡、三七,属于中药注射液。具有活血通经,祛瘀止痛的功效。临床用于治疗痛经,经闭,跌扑损伤,风湿痹痛等。
复方茵陈注射液在我国已在临床广泛应用多年,临床疗效得到了医患双方的好评。但近年来,中药注射液临床应用的不良反应报道日趋严重,影响了具有中国医药特色的中药注射液的发展。国内专家学者对中药注射液的不良反应进行了大量研究,文献报道其不良反应的发生与中药注射液中加入的存在安全隐患的助溶剂聚山梨酯80(吐温80)有很大的关系。由于中药注射液成分复杂,在贮存和高温灭菌过程中易出现溶质析出而影响澄明度、溶液pH值明显下降等问题,因此在该类注射液中加入了聚山梨酯80(吐温80)作助溶剂,加入其他助溶剂的助溶效果则不明显。但聚山梨酯80(吐温80)由于精制工艺不成熟,在贮存和高温灭菌过程中容易酸败,导致杂质含量高,难以达到注射用标准,聚山梨酯80(吐温80)本身就具有较强的溶血性和过敏性,应用在注射液中增加了发生不良反应的几率和风险。另外,中药注射液在灭菌和贮存过程本身还存在溶液pH值明显下降的问题,而聚山梨酯80(吐温80)又容易酸败,更加速了药液的pH值的下降。目前国内生产的复方茵陈注射液中也加入了聚山梨酯80(吐温80)作助溶剂,面临着同样的问题。
鉴于上述原因,寻找安全性更好、助溶效果更明显的助溶剂替换安全性差的聚山梨酯80(吐温80)是该注射液急需解决的问题。
发明内容
本发明所要解决的技术问题是提供一种安全性更好、助溶效果更明显的提高复方茵陈注射液安全性的药物组合物制备方法。
本发明解决上述技术问题所采用的技术方案是:一种提高复方茵陈注射液安全性的药物组合物,主要由茵陈提取物、春柴胡提取物、三七提取物和聚乙二醇十五羟基硬脂酸酯制成的供注射用药物组合物。
具体地,聚乙二醇十五羟基硬脂酸酯的用量为0.005g~5.0g/100ml;聚乙二醇十五羟基硬脂酸酯的用量优选为0.05g~1.0g/100ml。
上述药物组合物中还包括聚山梨酯80,聚乙二醇十五羟基硬脂酸酯与聚山梨酯80按不同比例联合作助溶剂,聚乙二醇十五羟基硬脂酸酯与聚山梨酯80的用量比例为0.005g~5.0g/100ml:0.001g~2.0g/100ml。
所述药物组合物剂型为注射液、粉针或冻干。
一种提高复方茵陈注射液安全性药物组合物的制备方法,包括下述步骤:
(1)复方茵陈注射液原料药材茵陈100g、春柴胡100g、三七100g,助溶剂2.0g;
(2)茵陈、春柴胡加水煎煮二次,每次2小时,合并煎液,加乙醇过滤浓缩,加3倍量水,充分搅拌,冷藏48小时,滤过,滤液减压浓缩至相对密度约为1.15,药液备用;
(3)三七加水煎煮二次,每次1小时,合并煎液,滤过,浓缩滤液,放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压浓缩至相对密度为1.20,加乙醇使含乙醇量为70%,静置过夜,滤过,滤液浓缩至相对密度为1.30,加3倍量水,充分搅拌,冷藏48小时,滤过,滤液浓缩至相对密度为1.15,
(4)与上述所有药液合并,加2倍量水,充分搅拌,冷藏24小时,滤过,滤液加入助溶剂和注射用水配制成1000ml溶液,搅匀,上述各滤液的相对密度均为80℃时的相对密度;
(5)用氢氧化钠溶液调节溶液pH值至6.5-8.5;
(6)过滤,灌装,灭菌,即得。
为了更好地实现本发明的方法,进一步地,所述步骤(1)中,助溶剂由聚乙二醇十五羟基硬脂酸酯与聚山梨酯80组成,其中聚乙二醇十五羟基硬脂酸酯的含量为0.005g~2.0g,余量为聚山梨酯80。
为了更好地实现本发明的方法,进一步地,所述步骤(2)中,加乙醇过滤浓缩的过程为,先过滤得滤液,滤液减压浓缩至相对密度为1.27~1.30,放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压回收乙醇并浓缩至相对密度为1.30。
为了更好地实现本发明的方法,进一步地,所述步骤(3)中,滤液浓缩至相对密度为1.25~1.30。
为了更好地实现本发明的方法,进一步地,所述步骤(5)中,使用的氢氧化钠溶液的质量百分数为20%。
为了更好地实现本发明的方法,进一步地,所述步骤(6)中,溶液使用微孔滤膜过滤。
本发明通过大量的实验研究,发现一种聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)是聚山梨酯80理想的替代产品。聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)已收载于欧洲药典(EP5.5)、德国药典和英国药典,可用于注射制剂的增溶剂。文献报道的药理毒理实验数据表明其毒性明显低于聚山梨酯80(吐温80)。另外我们通过大量的实验研究发现,达到相同的助溶效果时聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)的用量比聚山梨酯80(吐温80)低,更加提高了药物的安全性。
文献报道的药理毒理实验数据表明聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)的安全性比聚山梨酯80(吐温80)高,其毒性明显低于聚山梨酯80(吐温80)(见下表1-3)。在复方茵陈注射液中分别使用等量的(0.5g/100ml)聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)和聚山梨酯80(吐温80),安全性实验对比研究结果表明,使用等量的(0.5g/100ml)聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)组在溶血性、刺激性、过敏性和降低血压等毒副反应方面均明显比使用聚山梨酯80(吐温80)组低,通过本发明明显减少了复方茵陈注射液在临床应用中发生不良反应的几率和风险,提高临床用药的安全性。
综上,本发明的有益效果是:提供一种安全性更好、助溶效果更明显的助溶剂替换复方茵陈注射液中存在安全隐患和影响产品质量的助溶剂聚山梨酯80(吐温80);聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)的安全性比聚山梨酯80(吐温80)高而且用量更低,减少药物发生不良反应的几率和风险,提高临床用药的安全性。
具体实施方式
实施例1
制备方法:茵陈、春柴胡加水煎煮二次,每次2小时,合并煎液,滤过,滤液减压浓缩至相对密度为1.27~1.30(80℃),放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压回收乙醇并浓缩至相对密度为1.30(80℃),加3倍量水,充分搅拌,冷藏48小时,滤过,滤液减压浓缩至相对密度约为1.15(80℃),药液备用;三七加水煎煮二次,每次1小时,合并煎液,滤过,滤液浓缩至相对密度为1.25~1.30(80℃),放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压浓缩至相对密度为1.20(80℃),加乙醇使含乙醇量为70%,静置过夜,滤过,滤液浓缩至相对密度为1.30(80℃),加3倍量水,充分搅拌,冷藏48小时,滤过,滤液浓缩至相对密度为1.15(80℃),与上述药液合并,加2倍量水,充分搅拌,冷藏24小时,滤过,滤液加入聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)作助溶剂和注射用水配制成1000ml溶液。搅匀。用20%氢氧化钠溶液调节溶液pH值至6.5-8.5。将上述溶液经微孔滤膜滤过。灌装,灭菌,即得。
实施例2
制备方法:茵陈、春柴胡加水煎煮二次,每次2小时,合并煎液,滤过,滤液减压浓缩至相对密度为1.27~1.30(80℃),放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压回收乙醇并浓缩至相对密度为1.30(80℃),加3倍量水,充分搅拌,冷藏48小时,滤过,滤液减压浓缩至相对密度约为1.15(80℃),药液备用;三七加水煎煮二次,每次1小时,合并煎液,滤过,滤液浓缩至相对密度为1.25~1.30(80℃),放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压浓缩至相对密度为1.20(80℃),加乙醇使含乙醇量为70%,静置过夜,滤过,滤液浓缩至相对密度为1.30(80℃),加3倍量水,充分搅拌,冷藏48小时,滤过,滤液浓缩至相对密度为1.15(80℃),与上述药液合并,加2倍量水,充分搅拌,冷藏24小时,滤过,滤液加入聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)与吐温-80作助溶剂和注射用水配制成1000ml溶液。搅匀。用20%氢氧化钠溶液调节溶液pH值至6.5-8.5。将上述溶液经微孔滤膜滤过。灌装,灭菌,即得。
实施例3
制备方法:茵陈、春柴胡加水煎煮二次,每次2小时,合并煎液,滤过,滤液减压浓缩至相对密度为1.27~1.30(80℃),放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压回收乙醇并浓缩至相对密度为1.30(80℃),加3倍量水,充分搅拌,冷藏48小时,滤过,滤液减压浓缩至相对密度约为1.15(80℃),药液备用;三七加水煎煮二次,每次1小时,合并煎液,滤过,滤液浓缩至相对密度为1.25~1.30(80℃),放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压浓缩至相对密度为1.20(80℃),加乙醇使含乙醇量为70%,静置过夜,滤过,滤液浓缩至相对密度为1.30(80℃),加3倍量水,充分搅拌,冷藏48小时,滤过,滤液浓缩至相对密度为1.15(80℃),与上述药液合并,加2倍量水,充分搅拌,冷藏24小时,滤过,滤液加入聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)作助溶剂和注射用水配制成溶液。搅匀。用20%氢氧化钠溶液调节溶液pH值至6.5-8.5。将上述溶液经微孔滤膜滤过。分装成1000支,冷冻干燥,即得。
实施例4:
本发明的茵陈提取物、春柴胡提取物、三七提取物和聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)制成的供注射用药物组合物可通过以下技术方案实现的:
(1)复方茵陈注射液原料药材茵陈100g、春柴胡100g、三七100g,聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)2.0g;
(2)茵陈、春柴胡加水煎煮二次,每次2小时,合并煎液,滤过,滤液减压浓缩至相对密度为1.27~1.30(80℃),放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压回收乙醇并浓缩至相对密度为1.30(80℃),加3倍量水,充分搅拌,冷藏48小时,滤过,滤液减压浓缩至相对密度约为1.15(80℃),药液备用;三七加水煎煮二次,每次1小时,合并煎液,滤过,滤液浓缩至相对密度为1.25~1.30(80℃),放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压浓缩至相对密度为1.20(80℃),加乙醇使含乙醇量为70%,静置过夜,滤过,滤液浓缩至相对密度为1.30(80℃),加3倍量水,充分搅拌,冷藏48小时,滤过,滤液浓缩至相对密度为1.15(80℃),与上述药液合并,加2倍量水,充分搅拌,冷藏24小时,滤过,滤液加入聚乙二醇(PEG)十二羟基硬脂酸酯(Solutol)作助溶剂和注射用水配制成1000ml溶液。搅匀。
(3)用20%氢氧化钠溶液调节溶液pH值至6.5-8.5。
(4)将上述溶液经微孔滤膜滤过。
(5)灌装,灭菌,即得。
本发明中,助溶剂可以是聚乙二醇十五羟基硬脂酸酯,其用量为0.005g~5.0g/100ml中的任意值,如0.005g/100ml、0.01g/100ml、0.05g/100ml、1.0g/100ml、5.0g/100ml等;助溶剂也可以由聚乙二醇十五羟基硬脂酸酯与聚山梨酯80组成,其用量比例为0.005g~5.0g/100ml:0.001g~2.0g/100ml。
Claims (6)
1.一种提高复方茵陈注射液安全性药物组合物的制备方法,包括下述步骤:
(1)复方茵陈注射液原料药材茵陈100g、春柴胡100g、三七100g,助溶剂2.0g;
(2)茵陈、春柴胡加水煎煮二次,每次2小时,合并煎液,加乙醇过滤浓缩,加3倍量水,充分搅拌,冷藏48小时,滤过,滤液减压浓缩至相对密度约为1.15,药液备用;
(3)三七加水煎煮二次,每次1小时,合并煎液,滤过,浓缩滤液,放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压浓缩至相对密度为1.20,加乙醇使含乙醇量为70%,静置过夜,滤过,滤液浓缩至相对密度为1.30,加3倍量水,充分搅拌,冷藏48小时,滤过,滤液浓缩至相对密度为1.15,
(4)与上述所有药液合并,加2倍量水,充分搅拌,冷藏24小时,滤过,滤液加入助溶剂和注射用水配制成1000ml溶液,搅匀,上述各滤液的相对密度均为80℃时的相对密度;
(5)用氢氧化钠溶液调节溶液pH值至6.5-8.5;
(6)过滤,灌装,灭菌,即得。
2.根据权利要求1所述的一种提高复方茵陈注射液安全性药物组合物的制备方法,其特征在于,所述步骤(1)中,助溶剂由聚乙二醇十五羟基硬脂酸酯与聚山梨酯80组成,其中聚乙二醇十五羟基硬脂酸酯的含量为0.005g~2.0g,余量为聚山梨酯80。
3.根据权利要求1所述的一种提高复方茵陈注射液安全性药物组合物的制备方法,其特征在于,所述步骤(2)中,加乙醇过滤浓缩的过程为,先过滤得滤液,滤液减压浓缩至相对密度为1.27~1.30,放冷,加乙醇使含乙醇量为65%,静置过夜,滤过,滤液减压回收乙醇并浓缩至相对密度为1.30。
4.根据权利要求1所述的一种提高复方茵陈注射液安全性药物组合物的制备方法,其特征在于,所述步骤(3)中,滤液浓缩至相对密度为1.25~1.30。
5.根据权利要求1所述的一种提高复方茵陈注射液安全性药物组合物的制备方法,其特征在于,所述步骤(5)中,使用的氢氧化钠溶液的质量百分数为20%。
6.根据权利要求1所述的一种提高复方茵陈注射液安全性药物组合物的制备方法,其特征在于,所述步骤(6)中,溶液使用微孔滤膜过滤。
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